For more than 30 years, bone morphogenetic proteins (“BMPs”, “morphogens”, “osteoinductive proteins”), a particular subclass of the transforming growth factor-β (TGF-β) super family of proteins, have been studied to understand the role these proteins play not only in bone and cartilage formation but also in soft tissue regeneration (e.g., kidney, heart, eye) and to develop such understanding into clinically effective therapies (see, e.g., Hoffmann et al., Appl. Microbiol. Biotechnol., 57: 294-308 (2001); Reddi, J. Bone Joint Surg., 83-A(Supp. 1): S1-S6 (2001); U.S. Pat. Nos. 4,968,590; 5,011,691; 5,674,844; 6,333,312). In efforts to develop such BMP-based therapies to treat bone defects, it soon became clear that the preferred way to treat a bone defect would be to implant into a defect site some type of implantable matrix carrying an effective amount of a BMP.
Osteogenic BMPs applied locally support formation of new bone, cartilage, and ligaments. Currently, only a few BMP-based therapies have been approved for treating fractures. BMP-7 (OP-1) is manufactured and distributed for treatment of long bone non-union fractures by Stryker Biotech (Hopkinton, Mass., U.S.). BMP-2 is manufactured and distributed for long bone acute fractures by Wyeth Pharmaceuticals (Madison, N.J., U.S.) and for spinal fusions by Medtronic, Inc. (Minneapolis, Minn., U.S.). In each of these approved therapies, the BMP active ingredient is combined with a bovine-derived collagen matrix (bovine collagen type 1). Owing to its bovine source, the collagen must be highly purified to eliminate immunogenicity and viral contamination. Moreover, the bovine source of the collage also presents a risk of bovine spongiform encephalopathy (BSE, mad cow disease). Accordingly, the purification and processing necessary for the collagen matrix in the currently approved therapies adds considerable cost, which places these devices well beyond the means of many individuals throughout the world. Moreover, however low, the risk of BSE associated with bovine products may further limit patient acceptance of these commercially available BMP therapies. As even the purest of collagen preparations may stimulate an immune response in a patient, several new carriers have been tested, including hydroxyl apatite salts and several synthetic polymers. Such alternatives are not natural and may present their own problems, such as irritation of local tissue, immunogenicity, and unknown affects on cell and tissue physiology within a patient.
Although broad statements have been made for many decades about the possible use of many other substances as possible matrix-carriers for BMP therapies to treat bone defects, to date, only a few as those mentioned above have been developed or approved. Clearly, needs remain for effective and affordable means and methods of delivering osteogenic proteins to the sites of bone defects.